Arginine

ACE inhibitorsACE inhibitors: In humans, ACE inhibitors may enhance vasodilation and effects of L-arginine (137; 139). Based on experience with intravenous arginine, it is possible that the use of high-dose oral arginine might alter potassium levels in the body, especially in people with severe liver disease (132). This is a potential concern for individuals who take ACE inhibitors, which may increase potassium levels.

AnalgesicsAnalgesics: In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen®) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin® or Advil® with ibuprofen-arginate may increase the risk of toxic effects.

Antacids, H2 blockers, proton pump inhibitorsAntacids, H2 blockers, proton pump inhibitors: Due to the theoretical potential for L-arginine to increase gastrin, and thus stomach acid, L-arginine may reduce the effectiveness of these agents, although clinical evidence is lacking.

AntibioticsAntibiotics: In humans, arginine caused hyperkalemia (84; 85) and should theoretically be used cautiously with agents that may increase potassium, including certain anti-infective agents like trimethoprim-sulfamethoxazole and pentamidine. In human research, L-arginine had antibacterial effects in patients with tuberculosis (225; 226). According to results of meta-analyses, arginine supplemented diets reduced infection complications after surgery (227; 205). In vitro, L-arginine protected against the detrimental effects of Bartonella henselae; mechanisms of action included production of nitric oxide, by modulation of p38 kinase phosphorylation and by normalizing expression of genes (228).

Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In humans, L-arginine reduced platelet aggregation (91; 92; 93; 94; 95; 96; 97; 98). In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, such as the anticoagulant heparin.

AntihypertensivesAntihypertensives: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers.

Anti-inflammatoriesAnti-inflammatories: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with other agents that may increase potassium, such as nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., indomethacin, ibuprofen, ketorolac). In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen®) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin® or Advil® with ibuprofen-arginate may increase the risk of toxic effects.

AntilipemicsAntilipemics: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230). In humans, fenofibrate increased plasma levels of L-arginine (231). In humans, simvastatin had a lack of an effect on vasodilation induced by L-arginine (232). In patients with elevated plasma triglycerides, L-arginine enhanced the triglyceride-lowering effect of simvastatin (230).

AntimalarialsAntimalarials: In human research, recovery of endothelial function in patients with severe falciparum malaria was related to improvements in plasma L-arginine concentrations (30).

AntineoplasticsAntineoplastics: In humans, L-arginine decreased cytotoxicity associated with chemotherapeutic agents (78), and in colorectal cancer patients, L-arginine resulted in increased numbers of cell subsets within the tumor expressing CD16 and CD56 surface markers (233). In human research, arginine supplementation has been reviewed and appears to stimulate both anticancer effects and tumor growth (141).

Antiobesity agentsAntiobesity agents: In humans, L-arginine may have an additive effect to exercise, resulting in a further decrease in adipose fat mass, waist circumference, and the leptin:adiponectin ratio; preservation of fat free mass; and increased adiponectin levels (106).

Cardiac glycosidesCardiac glycosides: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis.

Cardiovascular agentsCardiovascular agents: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers. In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis. Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension. In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146).

ContraceptivesContraceptives: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235).

EstrogensEstrogens: In humans, estrogens found in birth control pills and hormone replacement therapies increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235).

Hormonal agentsHormonal agents: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235).

IsoproterenolIsoproterenol: In humans, vasodilation in response to isoproterenol was enhanced by L-arginine (265).

Neurologic agentsNeurologic agents: In mountain climbers, L-arginine increased risk of developing a headache (89). Headache has occurred in other clinical trials (90; 86). Anecdotally, headache following rapid intravenous administration has also been described. L-arginine can have both beneficial and deleterious effects in terms of ischemic damage, depending on time of administration, due to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular system (207).

NitratesNitrates: Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension.

NitroderivativesNitroderivatives: In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146).

Phosphodiesterase inhibitorsPhosphodiesterase inhibitors: Arginine should be used with caution with phosphodiesterase inhibitors (e.g., sildenafil [Viagra®]), due to the theoretical risk of additive vasodilation and hypotension. In animals, concurrent use of L-arginine and phosphodiesterase inhibitors, including sildenafil, resulted in synergistic effects and additive vasodilation (278). The effect of vardenafil, in addition to propionyl-L-carnitine, L-arginine, and nicotinic acid, has been examined in human research (279). Additive effects were lacking.

Potassium saltsPotassium salts: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including potassium supplements.

SertralineSertraline: In animals, L-arginine pretreatment reversed the protective effect of sertraline in terms of ischemia (281).

SpironolactoneSpironolactone: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including spironolactone. In a case report, spironolactone and arginine monohydrochloride resulted in marked hyperkalemia, with fatal cardiac arrhythmia (85).

AnalgesicsAnalgesics: In humans, a combination of ibuprofen and arginine had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin® or Advil® with ibuprofen-arginate may increase the risk of toxic effects.

AntacidsAntacids: Due to the theoretical potential for L-arginine to increase gastrin, and thus stomach acid, L-arginine may reduce the effectiveness of these agents.

AntibacterialsAntibacterials: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including certain anti-infective agents. In human research, L-arginine had antibacterial effects in patients with tuberculosis (225; 226). In human trials, arginine-supplemented diets reduced infection complications after surgery (227; 205). In vitro, L-arginine protected against the detrimental effects of Bartonella henselae (228).

Anti-inflammatoriesAnti-inflammatories: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with other agents that may increase potassium, such as nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., indomethacin, ibuprofen, ketorolac). In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen®) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin® or Advil® with ibuprofen-arginate may increase the risk of toxic effects.

AntilipemicsAntilipemics: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230).

AntimalarialsAntimalarials: In human research, recovery of endothelial function in patients with severe falciparum malaria was related to improvements in plasma L-arginine concentrations (30).

AntineoplasticsAntineoplastics: In humans, L-arginine decreased cytotoxicity associated with chemotherapeutic agents (78), and in colorectal cancer patients, L-arginine may result in increased numbers of cell subsets within the tumor expressing CD16 and CD56 surface markers (233). In human research, arginine supplementation has been reviewed and appears to stimulate both anticancer effects and tumor growth (141).

Antiobesity agentsAntiobesity agents: In humans, L-arginine had an additive effect to exercise, resulting in a further decrease in adipose fat mass, waist circumference, and the leptin:adiponectin ratio; preservation of fat free mass; and increased adiponectin levels (106).

Cardiac glycosidesCardiac glycosides: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis.

Cardiovascular agentsCardiovascular agents: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers, and agents that may increase potassium, including digitalis. Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension. In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146).

CitrullineCitrulline: In humans, serum citrulline may increase with L-arginine supplementation in some (129; 288) but not all studies (289; 290).

Conjugated linoleic acid (CLA)Conjugated linoleic acid (CLA): In animals, CLA and arginine were found to modulate adipose tissue metabolism by separate, but not additive, effects (39).

CreatineCreatine: In human research, there was a lack of effect of creatine on the actions of L-arginine on vascular function (152). Based on a review, treatment of guanidinoacetate methyltransferase (GAMT) deficiency required dietary restriction of arginine (120).

GinkgoGinkgo: In humans, a combination of Ginkgo biloba extract, arginine, and magnesium reduced healing times of trophic lesions in the lower limbs caused by microangiopathy, and improved symptoms (136).

Hormonal agentsHormonal agents: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235).

HypotensivesHypotensives: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers.

LysineLysine: Based on a systematic review, there is strong evidence for the use of herbal supplements containing combinations of L-lysine and L-arginine as treatments for anxiety symptoms and disorders (294). In humans, a combination of lysine and L-arginine increased adrenocorticotropic hormone, cortisol, adrenaline, and noradrenaline levels during psychological stress, and decreased basal trait and state anxiety scores and salivary cortisol and chromogranin A (53; 295). In humans, a combination of lysine and arginine had a lack of an effect on growth hormone levels (296). Theoretically, foods rich in arginine may result in a breakout of cold sores, thus reducing efficacy of lysine, traditionally used for cold sore treatment and prevention. In vitro, inotropic effects of L-lysine were not abrogated by L-arginine (297). In human research, L-arginine amplified the effect of a low-lysine diet; the authors suggested that this was due to competition with L-lysine at the blood-brain barrier (298).

MagnesiumMagnesium: In humans, a combination of Ginkgo biloba extract, arginine, and magnesium reduced healing times of trophic lesions in the lower limbs caused by microangiopathy, and improved symptoms (136).

Neurologic agentsNeurologic agents: In mountain climbers, L-arginine increased risk of developing a headache (89). Headache has occurred in other clinical trials (90; 86). Anecdotally, headache following rapid intravenous administration has also been described. L-arginine can have both beneficial and deleterious effects in terms of ischemic damage, depending on time of administration, due to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular system (207).

Omega-3 fatty acidsOmega-3 fatty acids: In humans, a combination of arginine, RNA, and omega-3 fatty acids reduced the length of hospital stays and infections after surgery in gastrointestinal cancer patients (300); increased in the number of T lymphocytes and subsets, helper T cells, and activated T cells (CD3 and HLA-DR); and increased interferon-gamma concentrations, and immunoglobulin M and immunoglobulin G levels (301). In animals, a combination of antioxidants (vitamin E, vitamin C), omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and L-arginine prevented the increased vascular response to phenylephrine in diabetic animals (277). In animals, supplementation with docosahexaenoic acid increased arginine concentrations in the brain, but not in liver or muscle (302).

PhytoestrogensPhytoestrogens: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235).

YohimbineYohimbine: In patients with mild-to-moderate erectile dysfunction, a combination of yohimbine and arginine improved erectile function (311). In women, vaginal pulse amplitude responses to an erotic film were increased with a combination of yohimbine and arginine (51).

Fats (cholesterol)Fats (cholesterol): In animals, dietary cholesterol increased levels of arginine in the brain, but not in liver or muscle (302).

SaltSalt: In humans, use of L-arginine may reduce renal sodium excretion with a low salt intake and increase renal excretion with a high salt intake (308). The saltiness of Gouda cheese was increased by L-arginine (313).

WatermelonWatermelon: In human research, watermelon was used as a source of L-citrulline (an L-arginine precursor) and L-arginine (1.3g of L-arginine in watermelon daily for six weeks) (314). In human and animal research, L-citrulline increased plasma L-arginine levels (292; 293).

XylitolXylitol: The sweetening agent xylitol can decrease the effect that arginine has on glucagon (249; 206).

Lipid profileLipid profile: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230). In humans, L-arginine modified levels of lipoprotein (a) using some, but not all, methods of analysis (340). In coronary stent patients, L-arginine reduced the levels of oxidative LDL cholesterol (102) or lag time to oxidation (271).

Nitric oxideNitric oxide: In humans, L-arginine increased levels of plasma or urinary nitric oxide or NO2 and NO3 (308; 93; 248; 246; 347; 214; 131; 130; 348; 349) or had a lack of an effect (350; 316). In humans, L-arginine increased exhaled nitric oxide (117; 118; 351) and general nitric oxide production (352). In animals, L-arginine increased blood levels of NO2 (353; 325) and decreased blood levels of NO3 and nitrogen oxide (325). In children, changes in exhaled nitric oxide after ingestion of L-arginine were considered to be of little clinical significance (354). In animal research, the authors suggested that L-arginine prevention of atherosclerosis may have been due to effects on plasma nitrite (355). Increased levels of nitric oxide metabolites have been shown in animal research (287). In exercising animals, L-arginine increased urinary nitrate excretion (356).

In vitro fertilizationIn vitro fertilization: L-arginine supplementation resulted in a lower cancelation rate of in vitro fertilization (IVF), an increased number of oocytes, an increased number of transferred embryos, and an improvement in follicular Doppler flow and pregnancy rate (167). In women undergoing IVF, arginine increased blood levels of arginine (208). In other research evaluating the effects of L-arginine in women undergoing IVF treatment, oral L-arginine supplementation in normally responding patients increased follicular recruitment and reduced the duration of pFSH treatment but had detrimental effects on embryo quality and pregnancy rate (208).

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.